Melasma is an acquired, chronic disorder of facial hyperpigmentation characterized by symmetric, irregularly bordered brown-to-gray-brown macules and patches, most commonly involving the malar eminences, forehead, and upper lip. It affects an estimated 1–33% of individuals depending on population and geographic latitude, with a striking female predominance and higher prevalence among Fitzpatrick skin types III–V. Its pathogenesis is multifactorial, involving ultraviolet and visible-light exposure, hormonal influences (pregnancy, oral contraceptives), genetic predisposition, and — increasingly recognized — a vascular and photoaging component, with dermal solar elastosis, an increased number of dilated blood vessels, and elevated vascular endothelial growth factor (VEGF) expression observed within melasma lesions.

This vascular hypothesis provided the rationale for repurposing tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid), a synthetic derivative of the amino acid lysine long used as an antifibrinolytic agent to control bleeding, as a treatment for melasma. TXA competitively inhibits the binding of plasminogen to keratinocytes, reducing plasmin activity, arachidonic acid release, and subsequent prostaglandin-mediated stimulation of melanocyte tyrosinase activity. In addition, TXA appears to reduce dermal vascularity and mast cell activity, both of which are increasingly implicated in melasma pathophysiology. First reported as an incidental finding in patients treated for other indications, oral TXA has since been evaluated extensively as a stand-alone and adjuvant melasma therapy, while intralesional (intradermal) microinjection has been developed as a means of delivering the drug directly to affected skin while theoretically limiting systemic exposure.

Given the chronic and relapsing nature of melasma and the imperfect efficacy of first-line topical agents such as hydroquinone and triple-combination creams, TXA — by whichever route — has become an important adjunct in modern melasma management protocols. However, oral and intralesional TXA differ substantially in their pharmacokinetics, treatment burden, cost, and risk profile, and direct comparative data are still accumulating. This review synthesizes the available comparative evidence, presents pooled and study-level statistical outcomes in tabular form, and discusses the practical implications for clinical decision-making.

A Cohort Analytical Study was conducted at the department of Dermatology in the Ibn-e-Siena Hospital Multan from 20TH April 2025 to 20th April 2026 and its protocol was registered prospectively in PROSPERO. The review question followed the PICO framework. The population was adults with clinically diagnosed melasma of any type and Fitzpatrick skin type. The intervention was intralesional tranexamic acid (TXA), delivered by microinjection or microneedling-assisted techniques, and the comparator was oral TXA at any reported dose. Studies comparing either route with placebo, topical agents, or hydroquinone were included as secondary comparisons. They evaluated intralesional TXA, oral TXA, or both, reported a validated severity measure such as the Melasma Area and Severity Index (MASI) or modified MASI (mMASI), and followed patients for at least eight weeks. Only English-language publications were considered, with no restriction on date. Case reports, small case series, editorials, conference abstracts without full data, narrative reviews, animal and in vitro studies, studies of topical TXA alone, and studies in which TXA was combined with other interventions so that its effect could not be isolated were excluded. The strategy combined controlled vocabulary and free-text terms for the condition ("melasma," "chloasma"), the intervention ("tranexamic acid," "TXA"), and the route of administration ("intralesional," "intradermal," "microneedling," "oral"), joined with Boolean operators. Two reviewers independently screened titles, abstracts, and full texts, resolving disagreements by discussion or through a third reviewer, and agreement was measured with Cohen's kappa. The selection process is presented in a PRISMA flow diagram. The primary outcomes were the change in MASI or mMASI from baseline to the end of treatment and the proportion of patients achieving a clinically meaningful response, defined as a reduction of at least 50%. Secondary outcomes included objective pigment measurements, patient satisfaction and quality of life, recurrence during follow-up, and time to response. Safety outcomes covered gastrointestinal symptoms, menstrual irregularities, visual disturbances, and thromboembolic events for oral TXA, and pain, erythema, bruising, post-inflammatory hyperpigmentation, and infection for intralesional TXA, along with dropout and discontinuation rates. The form captured study design, sample size, participant characteristics, melasma type and severity, dose, concentration, frequency, treatment duration, delivery technique, outcome measures, time points, and adverse events. Authors were contacted for missing data, and means and standard deviations were estimated from medians and ranges where necessary. Risk of bias was assessed with the Cochrane RoB 2 tool for randomized trials and ROBINS-I or the Newcastle-Ottawa Scale for non-randomized studies, and the certainty of evidence for each primary outcome was graded using the GRADE approach. Findings were first summarized narratively and in tables, organized by comparison and outcome. Where at least two sufficiently homogeneous studies reported the same outcome, results were pooled using a random-effects model. Continuous outcomes were expressed as mean or standardized mean differences and dichotomous outcomes as risk or odds ratios, each with 95% confidence intervals. Heterogeneity was assessed with the I² statistic, with values above 50% considered substantial. Subgroup analyses examined melasma type, baseline severity, dose, and treatment duration, and sensitivity analyses excluded high-risk studies. 2. Mechanism of Action and Rationale for Route Selection TXA acts on both the epidermal and dermal compartments implicated in melasma. By blocking the lysine-binding sites of plasminogen, it reduces conversion of plasminogen to plasmin in keratinocytes exposed to ultraviolet light, thereby diminishing downstream release of free arachidonic acid and prostaglandins (PGE2, PGF2-alpha), which are known melanocyte-stimulating mediators. TXA has also been shown to downregulate VEGF and endothelin-1 expression, reducing the abnormal dermal vascularity characteristic of melasma lesions, and to modestly inhibit tyrosinase activity in melanocytes directly. Oral administration achieves systemic plasma concentrations sufficient to exert this effect throughout affected and unaffected skin simultaneously, which may explain reports of a generalized lightening effect and, in some series, more rapid symptomatic improvement. Intralesional (microinjection or mesotherapy-style) administration delivers a concentrated dose directly into the papillary and superficial reticular dermis of pigmented lesions, aiming to maximize local drug concentration at the site of pathology while minimizing systemic absorption and the associated risk of antifibrinolytic adverse effects such as venous thromboembolism. This difference in delivery underlies the central clinical question addressed by comparative trials: does the theoretically favorable safety profile of intralesional therapy come at a cost of reduced, comparable, or superior efficacy relative to oral dosing? 3. Dosing and Administration Protocols Reported in the Literature 3.1 Oral Tranexamic Acid The most widely studied oral regimen is 250 mg administered twice daily, typically for 8 to 12 weeks, though doses ranging from 500 mg once daily to 500 mg twice daily and durations extending to 6 months have been reported. Oral TXA is generally used as monotherapy or, more commonly, as an adjunct to topical depigmenting agents and photoprotection. Pre-treatment screening for contraindications — personal or family history of venous thromboembolism, hypercoagulable states, concurrent oral contraceptive or hormone replacement use, and active malignancy — is recommended by most authors before initiating systemic therapy. 3.2 Intralesional (Intradermal) Tranexamic Acid Intralesional protocols vary considerably in concentration and technique. Reported regimens include microinjections of 4 mg/mL and 100 mg/mL TXA solutions, and manual point-injection or mesoneedling / microneedling-assisted delivery of TXA at concentrations equivalent to approximately 4 mg/mL, administered every two to four weeks for a total of four to eight sessions. A total dose per session is typically kept low (on the order of 10–20 mg per treated area in some protocols) to minimize discomfort, bruising, and the theoretical, though largely unconfirmed, risk of systemic absorption.

Comparative Clinical Evidence

Several randomized and quasi-experimental trials have directly compared oral and intralesional TXA, in addition to a larger body of literature evaluating each route against placebo, topical TXA, or other standard therapies (triple-combination cream, platelet-rich plasma, microneedling alone). Representative comparative and route-specific studies are summarized in Table 1.

Table 1. Representative Studies of Oral and Intralesional Tranexamic Acid in Melasma

4.1 Head-to-Head Efficacy

In the trial by El Hadidi and colleagues — the most direct three-arm comparison available — oral TXA (250 mg twice daily) and two concentrations of intradermal microinjected TXA all produced statistically significant reductions in mMASI and melanin index over eight weeks, with no single route demonstrating clear statistical superiority over the others, though the oral arm trended toward a numerically larger and more consistent reduction across secondary measures. A Pakistani quasi-experimental study comparing intralesional and oral TXA (250 mg twice daily) over three months similarly reported meaningful mMASI reduction in both arms, reinforcing that the two routes are broadly comparable in overall pigment-clearing effect, while intralesional therapy avoided the systemic exposure associated with oral dosing.

Where intralesional TXA has been compared against active topical comparators rather than oral TXA directly (e.g., triple-combination cream or Kligman's regimen), it has generally performed at least as well, and in some series achieved superior patient-reported quality-of-life improvement, as reflected in DLQI scores. This suggests that intralesional TXA's localized action on dermal vascularity and pigment may translate into meaningful clinical benefit even when systemic drug levels are minimal.

4.2 Onset and Durability of Response

Oral TXA is frequently reported to produce a more rapid initial reduction in erythema and pigment intensity, plausibly reflecting its immediate systemic anti-vascular effect, whereas intralesional protocols — being session-based and spaced two to four weeks apart — tend to show a more gradual, cumulative improvement. Both routes, however, are associated with relapse after treatment discontinuation; relapse rates of approximately 27% within months of stopping oral therapy have been reported in large retrospective cohorts, underscoring that TXA, regardless of route, functions as a suppressive rather than curative therapy and that maintenance strategies (photoprotection, intermittent re-treatment) remain essential.

5. Statistical Comparison of Reported Efficacy Outcomes

Table 2 consolidates quantitative efficacy data extracted from the studies with directly reported numerical outcomes, allowing side-by-side comparison of the magnitude and statistical significance of MASI/mMASI change achieved with each route.

Table 2. Quantitative Efficacy Outcomes by Route of Tranexamic Acid Administration

Because trials differ in baseline severity, scoring instrument (MASI vs. mMASI), treatment duration, and comparator arm, absolute scores are not directly poolable across studies; the table therefore reports each study's own within-arm or between-arm significance rather than a single composite effect size. Nonetheless, the consistent direction and statistical significance of effect across nearly every reported comparison — regardless of route — supports TXA's efficacy as a class, while the head-to-head trials (El Hadidi et al.; the oral-vs-intralesional Pakistani cohort) indicate that neither route has been convincingly shown to be statistically superior to the other for overall pigment reduction.

Table 3 presents raw baseline and end-of-treatment mean scores with standard deviations, as reported in the original publications, allowing direct inspection of the magnitude of numerical change achieved with oral versus intralesional/intradermal regimens.

Table 3. Numerical Statistical Summary — Baseline vs. Post-Treatment Scores (Mean ± SD)

Read together with Table 2, these figures show that both oral and intralesional/intradermal TXA regimens are capable of producing large, statistically significant absolute reductions in melasma severity scores — in several series exceeding a 60–85% reduction from baseline — while also illustrating that adding oral TXA to an already-active topical regimen does not always yield a statistically significant incremental benefit (Basit et al.), highlighting that patient selection, baseline severity, and concurrent therapy materially influence the numerical magnitude of response beyond route alone.

6. Safety and Tolerability

The safety profiles of oral and intralesional TXA differ qualitatively, reflecting their divergent pharmacokinetics, and this distinction is often more clinically decisive than small differences in efficacy.

6.1 Oral Tranexamic Acid

The most commonly reported adverse effects of oral TXA in melasma trials are gastrointestinal discomfort, headache, and menstrual irregularities (hypomenorrhoea or oligomenorrhoea), typically mild and self-limited. The adverse effect of greatest clinical concern is venous thromboembolism (VTE), given TXA's antifibrinolytic mechanism; however, at the low, short-course doses used for melasma (typically 500 mg/day for weeks to a few months), reported thromboembolic events are rare. A large retrospective cohort of 561 patients reported an overall adverse-event rate of 7.1%, including a single case of deep vein thrombosis in a patient later found to have an underlying familial protein S deficiency — underscoring the importance of pre-treatment risk screening rather than indicating a high baseline risk in unselected patients. A more recent multicenter propensity-score-matched electronic health record cohort found no significant association between oral TXA use for melasma and thromboembolic events compared with matched controls, providing reassuring real-world evidence for appropriately screened patients.

6.2 Intralesional Tranexamic Acid

Intralesional TXA is associated almost exclusively with local, procedure-related adverse effects: injection-site pain, pinpoint bleeding, bruising/ecchymosis, transient erythema, and, less commonly, localized urticaria or hyperpigmentation at injection sites. Because systemic absorption from intradermal microinjection is minimal, published series have not reported thromboembolic or other systemic antifibrinolytic complications. The principal drawbacks of the intralesional route are practical rather than pharmacological: procedural discomfort, the need for repeated clinic visits, operator-dependent technique, and a small risk of needle-related complications such as bruising or, rarely, infection.

Table 4. Comparative Safety Profile — Oral vs. IntralesionalTranexamic Acid

The accumulated evidence indicates that oral and intralesional tranexamic acid are both effective, evidence-supported options for melasma, with neither route demonstrating unambiguous superiority in head-to-head efficacy. This equivalence in outcome, combined with clearly differentiated safety and practicality profiles, means that route selection is best individualized rather than protocol-driven. Patients with risk factors for venous thromboembolism, those unable or unwilling to attend frequent injection visits, or those preferring a self-administered regimen may be better suited to a carefully screened oral course. Conversely, patients with contraindications to systemic antifibrinolytic therapy, those seeking to avoid any systemic drug exposure (for example, during breastfeeding, where data are limited), or those who tolerate injections well may benefit preferentially from intralesional therapy, which appears to carry a more favorable systemic safety margin at the cost of procedural burden and operator dependency.

A recurring theme across the literature is that TXA — by any route — performs best as part of a comprehensive melasma regimen rather than as monotherapy. Combination approaches pairing oral or intralesional TXA with photoprotection, topical depigmenting agents, or energy-based devices (such as low-fluence Q-switched Nd:YAG laser or fractional CO2) have shown additive benefit in several trials, suggesting that the choice of TXA route may matter less than ensuring it is embedded within a well-rounded, sun-protective treatment plan. Relapse after treatment cessation remains a near-universal finding regardless of route, reinforcing that melasma management is a long-term, maintenance-oriented endeavor.

From a cost and resource perspective, oral TXA is inexpensive, widely available, and does not require specialized equipment or training, making it attractive in resource-limited settings. Intralesional therapy requires trained personnel, sterile technique, and repeated in-office visits, increasing both direct and indirect costs, but may be preferred in settings where systemic antifibrinolytic exposure is a specific concern or where localized, targeted treatment of resistant patches is desired after an inadequate response to oral or topical therapy.

Limitations of the Current Evidence Base

• Most comparative studies have small sample sizes (typically 30–70 patients per trial), limiting statistical power to detect modest between-route differences.
• Heterogeneity in outcome instruments (MASI vs. modified MASI), TXA concentration/dose, treatment duration, and follow-up length hampers direct pooling of effect sizes across studies.
• Long-term data (beyond 6–12 months) comparing sustained remission rates between routes are sparse.
• Few trials are adequately powered or designed to detect rare adverse events such as thromboembolism, given its low baseline incidence at melasma-relevant doses.
• Blinding is difficult to achieve for intralesional therapy (visible injections/needling), introducing potential performance and detection bias relative to oral-drug trials, which can be more readily placebo-controlled.

Tranexamic acid, whether delivered orally or by intralesional microinjection, represents a valuable and well-supported addition to the therapeutic armamentarium for melasma. Comparative trials to date show broadly similar efficacy between the two routes in reducing MASI/mMASI scores, while safety and tolerability profiles differ meaningfully: oral therapy carries a small but real systemic risk, chiefly relevant in patients with thromboembolic risk factors, whereas intralesional therapy is limited mainly by local, self-limited procedural effects and greater treatment burden. Route selection should therefore be guided by individual patient risk factors, preferences, access to trained providers, and cost considerations, ideally within a broader treatment plan that emphasizes strict photoprotection and, where appropriate, combination with topical or device-based therapies. Larger, adequately powered, multi-ethnic randomized trials with standardized outcome measures and longer follow-up are needed to define optimal dosing, treatment duration, and maintenance strategies for both routes.Tranexamic acid, whether delivered orally or by intralesional microinjection, represents a valuable and well-supported addition to the therapeutic armamentarium for melasma. Comparative trials to date show broadly similar efficacy between the two routes in reducing MASI/mMASI scores, while safety and tolerability profiles differ meaningfully: oral therapy carries a small but real systemic risk, chiefly relevant in patients with thromboembolic risk factors, whereas intralesional therapy is limited mainly by local, self-limited procedural effects and greater treatment burden. Route selection should therefore be guided by individual patient risk factors, preferences, access to trained providers, and cost considerations, ideally within a broader treatment plan that emphasizes strict photoprotection and, where appropriate, combination with topical or device-based therapies. Larger, adequately powered, multi-ethnic randomized trials with standardized outcome measures and longer follow-up are needed to define optimal dosing, treatment duration, and maintenance strategies for both routes.